反应详情

To a −78° C. cooled solution of 2-{[5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-1-ethanol (710 mg) (Preparation 45) in anhydrous tetrahydrofurane (25 ml) under an atmosphere of nitrogen, was added sodium hydride (60% dispersion in oil, 113 mg) and the mixture was stirred for 10 minutes at this temperature before 5-chloro-2-(methylsulfonyl)pyrimidine (543 mg) was added in one portion and the mixture was stirred overnight at room temperature. The TLC indicated an incomplete reaction so the mixture was cooled to −78° C. and another portion of sodium hydride (60% dispersion in oil, 100 mg) was added. The mixture was stirred for 12 h at room temperature. Again, the TLC indicated an incomplete reaction. The mixture was cooled again to −78° C. and sodium hydride (60% dispersion in oil, 100 mg) was added. After 10 minutes at this temperature, 5-chloro-2-(methylsulfonyl)pyrimidine (200 mg) was added in one portion. The reaction was stirred overnight at room temperature. An aqueous saturated solution of ammonium chloride (1 ml) was carefully added before the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of water (20 ml) and dichloromethane (20 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2×20 ml). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 30 g) eluted with dichloromethane:methanol (95:5) yielding the title compound as a colourless oil (910 mg).

1. additionwas added in one portion
2. customan incomplete reaction so the mixture
3. temperaturewas cooled to −78° C.
4. stirringThe mixture was stirred for 12 h at room temperature
5. customan incomplete reaction
6. temperatureThe mixture was cooled again to −78° C.
7. stirringThe reaction was stirred overnight at room temperature
8. concentrationwas concentrated under reduced pressure
9. dissolutionThe residue was dissolved in a mixture of water (20 ml) and dichloromethane (20 ml)
10. customThe phases were separated
11. extractionthe aqueous phase was extracted with dichloromethane (2×20 ml)
12. dry with materialThe combined organic fractions were dried over sodium sulfate
13. concentrationconcentrated under reduced pressure
14. customThe residue was purified by column chromatography (silica, 30 g)
15. washeluted with dichloromethane:methanol (95:5)